OBJECTIVE: To evaluate the efficacy and safety of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in combination with radiotherapy (RT) for patients with advanced non-small cell lung cancer (NSCLC) harboring typical EGFR mutations. METHODS: Patients who received treatment with third-generation EGFR-TKIs alone or in combination with RT were retrospectively enrolled at a single center. The primary endpoint was progression-free survival (PFS). Differences in PFS between the two groups were assessed via the Kaplan-Meier method. Additionally, a subgroup analysis was conducted to further explore the effect of thoracic RT combined with EGFR-TKIs. RESULTS: This study included a total of 260 patients, among whom 81 patients received third-generation EGFR-TKIs and 179 patients received third-generation EGFR-TKIs plus RT. There was a significant difference in median PFS (mPFS) (13.0 versus 18.1 months, P = 0.0003) between the two groups. Moreover, third-generation EGFR-TKIs plus thoracic RT significantly improved the mPFS (13.0 versus 23.7 months, P <
0.0001). We observed that third-generation EGFR-TKIs plus RT increased the incidence of pneumonia, but all the cases were grade 1 or 2. CONCLUSION: The addition of RT can delay the occurrence of acquired resistance to third-generation EGFR-TKIs, thereby significantly prolonging PFS in advanced NSCLC patients. RT for primary lung lesions exhibited a significant synergistic effect with EGFR-TKI treatment, and the adverse events of the combination therapy were acceptable.